2.1. Tumor Necrosis Factor and its Pathophysiology PA0 2.2. Treatment of TNF-Associated Disorders
TNF was originally discovered as a molecule which caused hemorrhagic necrosis of mouse tumors (Carswell et al., 1975, Proc. Natl. Acad. Sci. U.S.A. 72:3666). A second line of investigation of a serum protein known as "cachectin", thought to be responsible for the condition of cachexia, led to the eventual discovery that cachectin was identical to TNF (Beutler et al., 1989, Annu. Rev. Immunol. 7:625). TNF has now been established as a broadly active inflammatory mediator involved in diverse clinical conditions.
TNF/cachectin was renamed as TNF-.alpha., and a structurally and functionally related protein previously known as lymphotoxin (LT) was referred as TNF-.beta. (Vassalli, 1992, Annu. Rev. Immunol. 10:411). Both molecules are active as homotrimers and mediate similar biological effects by binding to the same two cellular receptors of 55 kD (p55 or complex I) and 75 kD (p75) molecular weight (Smith et al., 1990, Science 248:1019; Schall et al., 1990, Cell 61:361). An LT heterotrimer was later discovered, which engaged a third receptor known as TNF-R related protein (rp), but it is not capable of binding to TNF-R p55 and p75 (Browning et al., 1993, Cell 72:847). This LT has been named as LT-.beta., and the LT homotrimer (or TNF-.beta.) is also referred to as LT-.alpha.. Structural comparison of the three TNF-R with several other cell surface receptors has resulted in the classification of these receptors into the TNF-R superfamily (Gruss and Dower, 1995, Cytokines and Mol. Ther. 1:75).
TNF-.alpha. is a 17 kD molecular weight protein produced by several cell types, particularly activated macrophages. Since TNF-R is expressed by numerous cell populations, TNF induces a wide variety of cellular responses, many of which result in deleterious consequences. For example, TNF induces cachexia which is a condition resulting from loss of fat and whole body protein depletion, accompanied by insufficient food intake due to anorexia. Cachexia is commonly seen in cancer patients, and it has also been observed in patients with acquired immunodeficiency syndrome (AIDS).
In addition, injection of high doses of TNF in animals produces most of the symptoms of septic shock. TNF has also been shown to play a role in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, hypersensitivity, immune complex diseases and graft versus host disease as well as transplantation rejection. The involvement of TNF has even been implicated in malaria and lung fibrosis.
Methods for neutralizing the adverse effects of TNF have focused on the use of anti-TNF antibodies and soluble TNF-R. In animal models, treatment of TNF-associated inflammatory disorders with antibodies specific for TNF has shown therapeutic efficacy (Williams et al., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:9784; Baker et al., 1994, Eur. J. Immunol. 24:2040; Suitters et al., 1994, J. Exp. Med. 179:849). Chimeric forms of anti-TNF antibodies have been constructed for use in human clinical trials (Lorenz et al., 1996, J. Immunol. 156:1646; Walker et al., 1996, J. Infect. Dis. 174:63; Tak et al., 1996, Arthritis Rheumat. 39:1077). Additionally, soluble TNF-R fusion proteins have been introduced as TNF-antagonists in human patients (Peppel et al., 1991, J. Exp. Med. 174:1483; Williams et al., 1995, Immunol. 84:433; Baumgartner et al., 1996, Arthritis Rheumat. 39(Suppl.) S74).
While the aforementioned approaches have shown some effectiveness in certain disease conditions, anti-TNF antibodies and soluble TNF-R both suffer from common limitations of macromolecules such as poor bioavailability and stability, induction of immune reactions and ineffective tissue penetration. Thus, there remains a need for improved therapeutic compounds for antagonizing the undesirable effects of TNF.